Colchicine clearance is impaired in alcoholic cirrhosis

Colchicine may have benefit in primary biliary cirrhosis and alcoholic liver disease. It is currently used in patients with impaired liver function, yet little is known about its elimination in such patients. Colchicine clearance in the rat is significantly impaired in various models of liver disease. To study this in human beings, colchicine pharmacokinetics were compared in normal subjects and patients with alcoholic cirrhosis. Colchicine clearance was impaired in the cirrhotic patients. Normal subjects had a mean clearance of 10.65 +/- 1.82 ml/min.kg, whereas cirrhotic patients had a mean clearance of 4.22 +/- 0.45 ml/min.kg (p less than 0.01). The half-life was 57.4 +/- 14.2 min in control subjects vs. 114.4 +/- 19.7 min in cirrhotic patients (p = 0.054). Volume of distribution was not different in the two groups (0.718 +/- 0.1 L/kg in control subjects; 0.716 +/- 0.158 L/kg in cirrhotic patients, p greater than 0.99). No correlation was seen between colchicine clearance and bilirubin, albumin, prothrombin time or Child-Pugh classification, but this may be the result of the small number of patients studied. Based on the values measured, it is estimated that colchicine steady state would change from an average 1.12 ng/ml in normal individuals to 2.82 ng/ml in the cirrhotic patients if 0.6 mg were taken every 12 hr. It is unknown whether this change would be clinically significant. These data show that cirrhosis impairs colchicine clearance and demonstrates that the liver is a major route of colchicine elimination.     

The effect of liver dysfunction on colchicine pharmacokinetics in the rat

Recent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P-450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham-operated controls), alpha-naphthylisothiocyanate-induced intrahepatic cholestasis and galactosamine-induced diffuse hepatocellular necrosis. The control group had a colchicine clearance of 77.33 ml/min.kg +/- 8.27 ml/min.kg, a half-life of 16.68 min +/- 0.97 min and a volume of distribution of 1.84 L/kg +/- 0.15 L/kg. Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p less than 0.05) and half-life to increase by 38% (p less than 0.05). Volume of distribution did not change. At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p less than 0.05), terminal half-life increased to 513.7 min +/- 106.6 min (p less than 0.05) and volume of distribution increased by 175% (p less than 0.05). Colchicine pharmacokinetics in sham-operated rats were not statistically different from the above mentioned controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Higher levels of serum aminoterminal type III procollagen peptide, and laminin in alcoholic than in nonalcoholic cirrhosis of equal severity.

In vitro models have shown that metabolites of ethanol (acetaldehyde and lactate) stimulate collagen synthesis, thereby, suggesting that they may be important as fibrogenic mediators. The relevance of these findings for fibrogenesis in the human liver in vivo, however, has not as yet been demonstrated. Serum markers for collagen (PIIINP, using radioimmunoassays employing polyclonal antibodies and Fab-fragments (PIIINP-Fab), respectively) and basement membrane (laminin) metabolism were therefore investigated in 25 alcoholic cirrhotics (Pugh-Score: 6.7 +/- 1.9 S.D.) and in 19 comparable nonalcoholic cirrhotics (Pugh-Score: 6.3 +/- 1.5, n.s.) with only slight evidence for inflammation: GOT 28 +/- 22 vs. 24 +/- 21 U/l; GPT 24 +/- 23 vs. 31 +/- 28 U/l; gamma-globulins 24 +/- 8 vs. 22 +/- 5%, respectively (all n.s.). Severity of the disease was assessed by quantitative liver function tests. Levels of PIIINP, PIIINP-Fab and laminin measured by RIA were 21 +/- 19 micrograms/l, 90 +/- 42 micrograms/l and 2.5 +/- 0.8 U/ml in alcoholic cirrhosis and 10 +/- 6 micrograms/l, 61 +/- 10 micrograms/l and 1.9 +/- 0.4 U/ml in nonalcoholic cirrhosis, respectively (all p less than 0.01). Differences on PIIINP and PIIINP-Fab remained significant even after accurate matching for galactose elimination capacity, aminopyrine breath test and hepatic sorbitol clearance. Laminin levels were higher in alcoholic cirrhosis only after matching for the hepatic sorbitol clearance (p less than 0.01). The higher levels of serum markers for collagen and basement membrane metabolism in alcoholic vs. nonalcoholic patients with cirrhosis at equal severity of the disease and with only minimal signs of inflammation may be the clinical reflection of a specific fibrogenic effect of ethanol metabolites.     

Comparison of lung vascular and epithelial permeability indices in the adult respiratory distress syndrome

Measurements of pulmonary clearance of inhaled 99mTc-DTPA and transvascular 113mIntransferrin flux were made in 12 patients with established ARDS and 14 volunteer control subjects (7 smokers and 7 nonsmokers). Smokers had significantly increased 99mTc-DTPA clearance (clearance rate constant, 3.6 +/- 0.8; mean +/- SEM) compared with nonsmokers (1.2 +/- 0.1). All patients with ARDS had increased clearance of 99mTc-DTPA (5.2 +/- 0.9), but the finding was nonspecific in that increased clearance overlapped with the findings in normal smokers. Protein flux in smokers (protein flux units, 0.0 +/- 0.2) was similar to that in nonsmokers (0.3 +/- 0.2). In 9 of the 12 patients with ARDS, protein flux was increased, and as a group (3.2 +/- 1.0) they differed significantly (p less than 0.01) from the combined smoking and nonsmoking control subjects (0.2 +/- 0.1, n = 14). The parameters of DTPA clearance and transvascular protein flux correlated well in the patients with ARDS (Spearman's rank correlation = 0.71, p less than 0.01). Although 99mTc-DTPA clearance is a sensitive technique in ARDS, a single study in this context does not allow a diagnostic conclusion because of its non-specificity. Abnormal protein flux appears to be more specific for ARDS but was not a universal finding in the patients studied.     

Fasting plasma caffeine level in cirrhotic patients: relation to plasma levels of catecholamines and renin activity

Fasting plasma caffeine concentrations, plasma levels of catecholamines and plasma renin activity were measured in patients with cirrhosis and control patients without hepatic dysfunction. A careful dietary history showed no significant difference in caffeine consumption (mean +/- S.E.) among 46 cirrhotics (86 +/- 7 mg per day) vs. 34 control patients (91 +/- 8 mg per day). Fasting plasma caffeine concentrations, however, were significantly higher (7.68 +/- 1.42 micrograms per ml) in cirrhotics than in controls (1.01 +/- 0.20 micrograms per ml) (p less than 0.01). Fasting plasma caffeine concentrations in cirrhotics varied significantly with Child's criteria, namely Child's A patients (2.06 +/- 0.38 micrograms per ml); Child's B patients (6.92 +/- 1.86 micrograms per ml), and Child's C patients (17.70 +/- 3.65 micrograms per ml) (p less than 0.001). In 44 cirrhotics, fasting plasma caffeine concentrations were compared with plasma levels of catecholamines and plasma renin activity. Plasma epinephrine concentrations were normal; however, plasma norepinephrine concentrations were increased in six cirrhotics, and plasma renin activities were increased in 28 cirrhotics. After a 3-day caffeine abstinence, plasma caffeine concentration and renin activity were significantly decreased (p less than 0.01), and high plasma norepinephrine levels were also decreased in 12 cirrhotics. Plasma caffeine concentration, renin activity and norepinephrine level did not change in a control group of cirrhotics who continued to receive caffeine for 3 days (n = 6). After abstinence from caffeine, the decrease of fasting plasma caffeine concentration correlated well with the decrease of plasma renin activity (r = +0.746, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of smoking on functional activity of plasma alpha 1-protease inhibitor

We determined the levels of alpha 1-protease inhibitor, the plasma trypsin-inhibiting capacity (TIC), and elastase-inhibiting capacity (EIC) in 29 nonsmokers and 30 smokers, who were healthy volunteers matched for age (mean age, 39 +/- 12 years [+/- SD]). The functional activity of plasma alpha 1-protease inhibitor (in micrograms of enzyme inhibited per microgram of alpha 1-protease inhibitor) was slightly but significantly lower in smokers, compared with nonsmokers, both for TIC and EIC (smokers' TIC and EIC were 88.0 +/- 16.2 percent (+/- SD) and 90.4 +/- 17.9 percent of the respective mean values in nonsmokers; p less than 0.05). Among smokers, there was a significant negative correlation (r = -0.37; p less than 0.05) between the average number of cigarettes smoked per day and the functional activity of plasma alpha 1-protease inhibitor; the seven subjects who smoked 40 or more cigarettes per day had significantly lower EIC and TIC than the remaining smokers. In 12 smokers tested before and after a two-hour period of intense smoking of eight cigarettes, there was a statistically significant decrease (p less than 0.05) in EIC one hour after smoking to 93.9 +/- 2.5 percent (+/- SE) of the initial value prior to smoking. It is concluded that there is a slight but significant decrease in the functional activity of plasma alpha 1-protease inhibitor in smokers, both for TIC and EIC.     

Caffeine clearance by enzyme multiplied immunoassay technique: a simple, inexpensive, and useful indicator of liver function.

The clinical value and sensitivity of serum caffeine clearance measurement has been evaluated as an indicator of hepatic disease. After a 17 hour caffeine exclusion period, 300 mg of caffeine citrate was administered orally to the study subjects. Serum samples were taken four and 16 hours later. Serum caffeine concentrations were measured using an enzyme multiplied immunoassay technique (EMIT) and a clearance value derived. Conventional liver function tests were measured at the same time. A total of 103 subjects attending the medical unit in a district general hospital were studied. Twenty one had alcoholic liver disease, 11 non-alcoholic cirrhosis, nine non-cirrhotic liver disease, 21 suspected liver disease, six hepatic tumours, and 35 were hospital and normal control subjects. Caffeine clearance values were lowest in subjects with alcoholic liver disease (median 0.19 ml/min/kg, range 0.04-0.61 ml/min/kg) and significantly reduced in all subjects with liver disease (median 0.32 ml/min/kg, range 0.04-2.68 ml/min/kg) compared with control subjects (median 1.27 ml/min/kg, p less than 0.001). In subjects with suspected liver disease subsequently shown to have another explanation for abnormal liver function test results, caffeine clearance values were normal (median 1.31 ml/min/kg, range 0.23-2.64 ml/min/kg) and significantly different, p less than 0.001, from those of subjects with liver disease. Serum albumen values were not different for these latter two groups. Using a cut off value of 0.86 ml/min/kg, caffeine clearance measurement was 100% sensitive for alcoholic liver disease and 89% sensitive for all liver disease. The respective sensitivities for conventional liver function test measurement were 76% and 83%. In the suspected liver disease group, caffeine clearance was abnormal in only 24%, conventional liver function tests were abnormal in 95%. The respective specificities for caffeine clearance and liver function test measurement in control subjects were 93% and 100%. Caffeine clearance determined by EMIT is a simple inexpensive hepatic metabolic function test. This study indicates that it is a more sensitive indicator of structural liver disease than conventional liver function tests, especially for alcoholic liver disease. The test could be widely introduced as a useful, repeatable assessment of hepatic function.     

Impaired liver function in stable renal allograft recipients

Hepatic failure as a cause of death is increased in stable renal allograft recipients when compared with patients on dialysis. In order to assess the magnitude and the natural history of the hepatic functional derangement, the kinetics of xenobiotics which are metabolized by cytosolic (galactose) or microsomal (prednisolone, cyclosporine A) enzymes were determined in 28 consecutive stable kidney transplant patients 1 month and 1 year after transplantation. Renal transplant patients had a decreased mean (+/- S.D.) galactose elimination capacity at 1 month (6.26 +/- 0.94 mg per min x kg) and at 1 year (5.93 +/- 0.96 mg per min x kg), when compared with a different group of 28 healthy control subjects (7.52 +/- 0.78 mg per min x kg, p less than 0.001) and a decreased total body clearance of prednisolone at 1 month (2.13 +/- 0.34 ml per min x kg vs. 2.71 +/- 0.43 ml per min x kg in controls, p less than 0.001), which further decreased over the following year to 1.76 +/- 0.32 ml per min x kg (p less than 0.001). The clearance of cyclosporine A declined significantly during the first year of successful transplantation (5.9 +/- 2.1 ml per min x kg vs. 4.9 +/- 1.2 ml per min x kg, p less than 0.05). In conclusion, a substantial proportion of stable renal transplant recipients have decreased cytosolic and microsomal liver functions despite the absence of clinical and laboratory evidence of significant liver disease.     

Thyrotropin-releasing hormone (TRH)-induced growth hormone (hGH) responses in cirrhotic men.

The plasma growth hormone (hGH) responses to an intravenous challenge of 400 micrograms of thyrotropin-releasing hormone (TRH) were evaluated in 14 normal controls and in 29 chronic alcoholic men. The normal controls had either a minimal or no hGH response to TRH, having basal hGH levels of 0.9 +/- 0.2 ng per ml and peak hGH levels of 2.0 +/- 0.5 ng per ml. In contrast, the chronic alcoholic men had a basal hGH level of 2.8 +/- 0.4 ng per ml, 3 times the basal level of the normal controls (P less than 0.01). The peak hGH response of the alcoholic men was 7.4 +/- 1.5 ng per ml (P less than 0.01). The 29 alcoholic men could be divided into two groups based upon the presence or absence of cirrhosis as determined by liver biopsy. The 16 alcoholic men with cirrhosis had greater basal hGH levels (3.5 +/- 0.6 ng per ml) and peak hGH levels (9.5 +/- 2.3 ng per ml) than did the 13 alcoholic men without cirrhosis (basal hGH 2.1 +/- 0.6 ng per ml, peak hGH 4.9 +/- 1.5 ng/ml). Plasma estradiol levels were similar in the normal controls and in the alcoholic men. In contrast, plasma estrone was greater in the alcoholic men (32.2 +/- 3.5 pg per ml) than in the normal controls (18.9 +/- 1.8 pg per ml) (P less than 0.05). However, when the plasma estrone levels of alcoholic men with cirrhosis were compared to those of the alcoholic men without cirrhosis no difference existed. Thus it is difficult to ascribe the increased hGH responses of the cirrhotic alcoholic men when compared to those of the noncirrhotic alcoholic men as being a result of increased basal estrogen levels.     

Metronidazole pharmacokinetics in patients with hepatic encephalopathy

The pharmacokinetics of metronidazole and its major metabolites was investigated in eight patients with liver cirrhosis and coma of grade 2 to 4 and in eight healthy controls. In the coma patients the systemic clearance of metronidazole was reduced (29 +/- 10 versus 83 +/- 14 ml/min, mean +/- SD; p less than 0.001) and the elimination half-life prolonged (20 +/- 9 versus 7.3 +/- 0.9 h; p less than 0.001), whereas the volume of distribution at steady state was unchanged (44 +/- 9 versus 48 +/- 7 l) as compared with the healthy controls. Investigation of the major elimination pathways of metronidazole showed that the decreased rate of elimination in the patients was mainly due to impaired hepatic drug oxidation. In four patients therapeutic plasma concentrations were achieved during 6 days' treatment with 500 mg metronidazole per 24 or 48 h.     

Assessment of hepatic function. Comparison of caffeine clearance in serum and saliva during the day and at night

Hepatic microsomal function was assessed by a caffeine clearance test at night and during the day using saliva and serum samples obtained simultaneously. In 26 patients with cirrhosis, 21 patients with noncirrhotic liver disease and 15 control subjects caffeine elimination correlated well during the day and at night (r = 0.915 for serum and 0.917 for saliva). The correlation coefficients for caffeine clearance in saliva and serum were 0.940 during the day and 0.963 overnight. In the cirrhotic patients, clearance differed significantly from noncirrhotic liver disease and controls in saliva samples overnight: 0.51 +/- 0.45 ml/min per kg versus 0.91 +/- 0.44 and 1.41 +/- 0.56, respectively. Comparable results were obtained for serum clearance overnight and clearances during the day. Serum and saliva clearances at night correlated well with the aminopyrine breath test (rs = 0.884 and 0.907, respectively). Overnight caffeine clearance in saliva might be a simple useful method for assessing progression and prognosis of liver disease.     

Glycerol clearance in alcoholic liver disease.

Glycerol clearance was studied by a primed dose-constant infusion technique in 14 patients with alcoholic liver disease and six normal control subjects. Fasting blood glycerol concentrations were raised in the alcoholic subjects (0.09 +/- 0.01 vs 0.06 +/- 0.01 mumol/l, p less than 0.05) and glycerol clearance was impaired (24.5 +/- 1.9 vs 37.5 +/- 3.2 ml/kg/min, p less than 0.005). Endogenous production rate of glycerol and distribution space at steady state were similar in alcoholic and control subjects. The metabolic clearance rate of glycerol correlated negatively with basal glycerol concentrations. Thus tissue uptake of glycerol is impaired in liver disease. As glycerol is metabolised primarily in the liver by conversion to glucose, these data suggest a defect of gluconeogenesis in alcoholic liver disease.     

Effect of portacaval shunt on drug disposition in patients with cirrhosis

To examine the consequences of liver blood flow variations on drug disposition in cirrhosis, we studied the effects of portacaval shunt on drug clearance in 35 cirrhotic patients. Lidocaine clearance and bioavailability, indocyanine green (ICG) clearance, aminopyrine breath test, and hepatic blood flow were measured before and 18 months after surgery. The patients were divided into two groups according to severity of disease: 14 patients (group 1) had slight liver dysfunction (ICG extraction ratio greater than 0.25) and 21 patients (group 2) had severe liver disease (ICG extraction ratio less than 0.25). After portacaval shunt the decrease in hepatic blood flow was similar for both groups (-65%). In group 1, ICG systemic clearance decreased from 9.10 +/- 0.68 to 4.40 +/- 0.34 ml/min . kg (p less than 0.05), whereas ICG intrinsic clearance remained unchanged; lidocaine systemic clearance decreased from 7.93 +/- 0.93 to 5.09 +/- 0.33 ml/min . kg (p less than 0.05), whereas lidocaine intrinsic clearance remained unchanged; bioavailability increased from 0.601 +/- 0.076 to 1, resulting in an abrupt reduction of oral clearance from 18.01 +/- 4.90 to 5.09 +/- 0.33 ml/min . kg (p less than 0.05). In group 2, ICG systemic clearance decreased slightly from 3.90 +/- 0.39 to 2.28 +/- 0.16 ml/min . kg (p less than 0.01) and ICG intrinsic clearance was not modified; lidocaine systemic and intrinsic clearance remained unchanged; and bioavailability increased from 0.779 +/- 0.229 to 1, resulting in a decrease of oral clearance from 7.68 +/- 1.65 to 4.23 +/- 0.37 ml/min X kg (p less than 0.05). The aminopyrine breath test was not affected by surgery in either group. We conclude that reduction of hepatic blood flow after portacaval shunt has only minimal effects on drug disposition in patients with severe liver disease, but results in a notable reduction in the clearance of high-extraction drugs in cirrhotics with mild liver disease.     

Increased nitric oxide output from alveolar origin during liver cirrhosis versus bronchial source during asthma

The aim of this study was to assess the usefulness of nitric oxide (NO) output measurement at multiple expiratory flow rates during diseases characterized by increased exhaled NO (FE(NO)) that could come from alveolar (liver cirrhosis) or bronchial (asthma) sources. It has been proposed that NO output measurements expressed as a function of expiratory flow allow alveolar NO concentration (FA(NO)) and maximal bronchial NO output (Qbr,max (NO)) to be computed. In 36 healthy nonsmoking subjects, we found that maximal bronchial NO output (37 +/- 3 nl/min) was correlated with the height of the subjects (p = 0.02). Alveolar NO concentration was 5.1 +/- 0.3 (SEM) ppb, which represented 31 +/- 2% and 61 +/- 3% of FE(NO) at 50 and 200 ml/s expiratory flow rate, respectively. Nonsmoking subjects with asthma (n = 28) were characterized by an increase in Qbr,max (NO) (133 +/- 14 nl/min) as compared with healthy nonsmoking subjects (p < 0.0001). FE(NO)50, FE(NO)200, and Qbr,max (NO) were equally efficient in differentiating subjects with asthma from healthy subjects. Patients with liver cirrhosis (n = 26, 14 smokers and 12 nonsmokers) had an increased FA(NO) compared with healthy subjects (cirrhosis: 8.3 +/- 0.9 ppb, healthy nonsmokers [n = 36] and smokers [n = 20], n = 56: 4.7 +/- 0.3 ppb, p < 0.05), which was correlated with the alveolar-arterial oxygen difference (p = 0.007). FA(NO) and FE(NO)200, but not FE(NO)50 values, allowed patients with liver cirrhosis to be differentiated from healthy subjects. These results suggest that a two-compartment model for NO output allows the increase in FE(NO) from alveolar sources to be differentiated from the increase from bronchial sources.     

Acute effect of smoking on the functional activity of alpha1-protease inhibitor in bronchoalveolar lavage fluid

To assess the acute effect of smoking on the functional activity of alpha1-protease inhibitor (alpha-Pl) in bronchoalveolar lavage (BAL), we studied 38 smokers (mean age 25 +/- 6.5 yr), who had 2 fiberoptic bronchoscopic lavages in sequence, the first after 8 h of abstinence from smoking, and the second at varying time intervals after smoking. Twenty-two smokers were tested before, and 10 min to 3 h after, smoking 2 medium-tar filter cigarettes; 16 smokers were were tested before, and 2 min to 60 min after, smoking 4 cigarettes. Eight nonsmoking volunteers had 2 BAL performed in sequence as control subjects. Initial BAL from control subjects and from smokers after 8 h of abstinence had similar alpha-Pl activity (mean 0.495 +/- SD 0.017 micrograms of pancreatic elastase/micrograms alpha-Pl, about 90% of the activity of purified alpha-Pl). After smoking, we did not find significant inactivation of alpha-Pl except in the 6 smokers lavaged 1 h after smoking 2 cigarettes, whose alpha-Pl activity decreased slightly to 90.0 +/- SD 10.6% of their initial activity (p less than 0.05). We also obtained BAL from 7 smokers only after smoking, and did not find inactivation of alpha-Pl. We conclude that in young healthy smokers: (1) alpha-Pl in BAL after 8 h of abstinence from smoking is active similar to nonsmoking control subjects, and (2) after smoking 2 to 4 cigarettes, there is no, or very limited, inactivation of alpha-Pl.     

Pharmacokinetics of Famotidine after Intravenous Administration in Liver Disease

The pharmacokinetics of famotidine were studied after the administration of a single intravenous dose of 20-mg to seven normal volunteers, six patients with chronic hepatitis, 14 patients with compensated cirrhosis, and seven patients with decompensated cirrhosis. The plasma terminal elimination half-life of famotidine was significantly prolonged and famotidine total body clearance was significantly reduced in patients with decompensated cirrhosis, whose creatinine clearance was 57.2 +/- 6.7 ml/min/1.48 m2, but these changes were not significant in patients with chronic hepatitis (creatinine clearance: 109.2 +/- 10.5 ml/min/1.48 m2) or in patients with compensated cirrhosis (creatinine clearance: 72.2 +/- 26.5 ml/min/1.48 m2 in comparison with normal volunteers. The total volume of distribution at steady state was not significantly different between the normal volunteers and the three groups of patients. Famotidine total body clearance showed a weak but significant correlation with the creatinine clearance (r = 0.66, p less than 0.001), serum albumin level (r = 0.51, p less than 0.01), and serum total bilirubin level (r = 0.36, p less than 0.05), which suggested that the reduction in clearance was due in part to the concomitant renal impairment, as well as hepatic dysfunction in these patients. In conclusion, famotidine total body clearance was reduced in decompensated cirrhosis, indicating that the dose schedule requires modification in patients with this condition.     

Overnight salivary caffeine clearance: a liver function test suitable for routine use

The feasibility of measuring caffeine clearance from saliva (SCl) was assessed in ambulatory patients with liver disease and in a control group, and the results were compared with quantitative liver function tests. For this purpose, the subjects were given 280 mg caffeine p.o. in decaffeinated coffee powder between noon and 4 p.m., and caffeine concentrations were measured in saliva (using an enzyme immunoassay) before bedtime and upon arising. In the cirrhotics (n = 29), SCl was 0.58 +/- S.D. 0.45 ml per min X kg, thus being reduced to approximately one-third of drug-free, nonsmoking controls (1.53 +/- 0.46, n = 18); although patients with noncirrhotic liver disease showed intermediate values (0.95 +/- 0.47), their reduction in SCl was significant (p less than 0.001). SCl was correlated with indocyanine green fractional clearance, galactose elimination capacity and aminopyrine breath test; however, the closest relationship (Rs = 0.80) was observed with the aminopyrine breath test. It is suggested that the measurement of SCl represents a noninvasive and innocuous procedure for quantifying hepatic microsomal function, and is suitable for routine use. Since a.m. saliva concentrations of caffeine are highly correlated (Rs = -0.94) with SCl, further simplification of the test to a single-point measurement appears possible.     

Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol.

Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.     

Elevation of chemotactic factor inactivator in alcoholic liver disease

Defective regulation of neutrophil chemotaxis occurs in patients with alcoholic liver disease. One potent mediator of neutrophil chemotaxis is the complement-derived neutrophil chemoattractant, C5a, which can be inhibited by a serum protein, chemotactic factor inactivator. We hypothesized that chemotactic factor inactivator elevation might, in part, explain the defective neutrophil chemotaxis seen in patients with alcoholic hepatitis. To test this hypothesis, sera were collected from 22 patients with alcoholic hepatitis and 9 normal controls, and evaluated for the antigenic presence of chemotactic factor inactivator using an ELISA test. Chemotactic factor inactivator levels were found to be markedly elevated in patients with alcoholic hepatitis (162 +/- 24 micrograms per ml) compared to normals (60 +/- 3 micrograms per ml, p less than 0.01). Subdividing the hepatitis patients revealed that the elevation of chemotactic factor inactivator was found to be greatest in those patients with mild alcoholic hepatitis (prothrombin time within normal limits and bilirubin less than or equal to 5 mg per dl, 256 +/- 44 micrograms per ml, p less than 0.001), while the group with the severest hepatic dysfunction (prolonged prothrombin time and bilirubin greater than 5 mg per dl) did not differ significantly from controls (71 +/- 11 micrograms/ml, p less than 0.2). Importantly, the inhibition of C5a-induced chemotactic activity by partially purified chemotactic factor inactivator correlated with antigenic amounts of chemotactic factor inactivator in serum (r = 0.63, p less than 0.05). The C5a inhibitory activity in sera obtained from patients with alcoholic hepatitis coprecipitated with chemotactic factor inactivator when serum was precipitated by ammonium sulfate precipitation (45 to 64% saturation).(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum type III procollagen peptide and laminin (Lam-P1) detect alcoholic hepatitis in chronic alcohol abusers

The diagnosis of alcoholic hepatitis is difficult to establish by conventional clinical and laboratory methods, and a firm diagnosis relies on liver histology. Since there are severe limitations in following patients with repeated liver biopsies, noninvasive procedures are needed to assess the presence of alcoholic hepatitis in chronic alcohol abusers. It has been suggested that serum Type III procollagen peptide levels correlates with the degree of inflammation in chronic liver disease. Since inflammation is a major histological finding in alcoholic hepatitis, we therefore studied the usefulness of measuring serum Type III procollagen peptide and laminin values in 45 consecutive chronic alcohol abusers, with or without cirrhosis, in detecting those with alcoholic hepatitis. The results showed that both Type III procollagen peptide and laminin values were elevated in all of the patients with established liver damage. However, the values were highest in those with liver cirrhosis plus alcoholic hepatitis (Type III procollagen peptide 50.4 +/- 36.4 ng per ml vs. 8.1 +/- 2.6 in controls, p less than 0.01; laminin 4.50 +/- 1.49 units per liter vs. 1.24 +/- 0.26 units per liter in controls, p less than 0.01), followed by subjects with alcoholic hepatitis alone (Type III procollagen peptide 23.5 +/- 17.6 ng per ml, p less than 0.01; laminin 2.60 +/- 1.09 units per liter, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)